1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts thereof has nerve protective action, nerve regeneration promotion action and neurite outgrowth action, and is a useful compound as remedies for central nervous system and peripheral nerve diseases.
As processes for production of this compound, for example, (1) a process of reacting 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene with 3-azetidinol or salts thereof, (2) a process of subjecting 1-(3-(2-(1-benzothiophen-5-yl)ethoxy) propionyl)azetidin-3-ol obtained from 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts thereof to reduction reaction with borane-tetrahydrofuran complex or subjecting it to reduction reaction with sodium borohydride in the presence of boron trifluoride complex tetrahydrofuran complex, and so forth are known (patent document 1).
However, the process of (1) has the following defects, (A) the yield is low, (B) complicated procedures of purification such as silica gel column chromatography are necessary, (C) therefore, a lot of waste is egested, and so forth.
In addition, the process of (2) cannot be satisfied as an industrial manufacturing process, because the process has the following defects, (A) the process uses reagents of borane-tetrahydrofuran complex and boron trifluoride tetrahydrofuran and so forth, which are harmful to human body, highly flammable, highly toxic and having problems of stability, (B) therefore, attention is necessary to handle and store it and special equipments are required, and so forth.
In addition, as a process for production of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or salts thereof used in (2) mentioned above, for example, the following processes are known, (3) a process of subjecting 2-(1-benzothiophen-5-yl)ethanol to Michael addition reaction with tert-butyl acrylate, subsequently subjecting it to de-tert-butylation, (4) a process of subjecting 2-(1-benzothiophen-5-yl)ethanol to Michael addition reaction with acrylonitrile, subsequently subjecting it to hydrolysis with acid, and so forth (patent document 1).
However, the processes of (3) and (4) cannot be satisfied as industrial manufacturing processes, because these processes have the following defects, the process of (3): (A) by-products form because of the occurrence of trans-esterification of acrylic acid, (B) special equipments and treatments are required because of the occurrence of a large quantity of combustible isobutene gas in de-tert-butylation reaction, the process of (4): the yield of hydrolysis with acid is low, and so forth.
As a process for production of 2-(1-benzothiophen-5-yl)ethanol used in (3) and (4) mentioned above, for example, the following processes are known, (5) a process of subjecting 5-methyl-1-benzothiophene to bromination with N-bromosuccinimide and to reaction with cyano compounds to obtain (1-benzothiophen-5-yl)acetonitrile, subsequently subjecting it to hydrolysis, subsequently subjecting it to reduction reaction (non-patent document 1, 2, 3), (6) a process of reacting 5-bromo-1-benzothiophene with magnesium to obtain Grignard reagent, subsequently subjecting it to reaction with ethylene oxide (patent document 2), (7) a process of subjecting 5-(1-benzothiophene)carbaldehyde to Wittig reaction with methoxymethylene ylide, subsequently subjecting it to hydrolysis to obtain (1-benzothiophen-5-yl)acetaldehyde, subsequently subjecting it to reduction reaction, and so forth (patent document 3).
However, the processes of (5) to (7) cannot be satisfied as industrial manufacturing processes, because these processes have the following defects, (A) intermediates have a stimulatory property, (B) a highly toxic reagent (cyano compounds) is used, (C) a carcinogenic reagent (ethylene oxide) is used, (D) highly ignitable reagents (butyllithium, Grignard reagent) are used, (E) procedures of the reaction are complicated, and so forth.
On the other hand, as processes for production of benzothiopheneacetic acid derivative or salts thereof, for example, the following processes are known, (8) a process of subjecting the hydroxyl group of benzothiophenemethanol to halogenation, subsequently subjecting it to reaction with cyano compounds to obtain benzothiopheneacetonitrile, subsequently subjecting it to hydrolysis (non-patent document 3), (9) a process of subjecting 7-oxo-4,5,6,7-tetrahydrobenzothiophene produced from 3-bromothiophene to Reformatsky reaction with ethyl bromoacetate, subsequently subjecting it to aromatization by dehydrogenation by use of sulfur, and subjecting it to hydrolysis, and so forth (non-patent document 4).
However, the processes of (8) and (9) cannot be satisfied as industrial manufacturing processes, because these processes have the following defects, (A) intermediates have a stimulatory property, (B) a highly toxic reagent (cyano compounds) is used, (C) therefore, complicated treatments of waste are required, (D) there are many steps of the process (E) the yield is low, (F) the reaction temperature is high, (G) procedures of the reaction are complicated, and so forth.
In addition, as a process for production of 5-halogeno-1-benzothiophene derivative, for example, the following processes are known, (10) a process of reacting 4-halogenothiophenol with 2-halogenoacetaldehyde dimethylacetal in the presence of base to obtain 2-(4-halogenophenylthio)acetaldehyde dimethylacetal, subsequently subjecting it to intramolecular ring closure reaction in the presence of polyphosphoric acid, and so forth (non-patent document 5, patent document 4, patent document 5).
However, the process of (10) cannot be satisfied as an industrial manufacturing process, because the process has the following defects, (A) complicated procedures such as distillation or silica gel column chromatography and so forth are necessary to isolated because the production intermediates are oily substances, (B) treatments of the process are complicated in ring closure reaction by use of phosphate compound because complicated by-products form, (C) complicated procedures such as distillation or silica gel column chromatography and so forth are necessary to separate 5-halogeno-1-benzothiophene derivatives from formed by-products because their derivatives have low melting points, (D) a large quantities of liquid waste is formed, which contains phosphorus compounds that require complicated procedures for treatment, and so forth.
As 4-halogenothiophenol used in (10) mentioned above, for example, (11) a process of subjecting thioanisole to halogenation with chlorine or bromine, subsequently subjecting it to demethylation with large excess of chlorine (patent document 6), (12) a process of reacting (4-halogenophenylthio)acetic acid with sodium sulfide in the presence of sodium hydroxide (patent document 7), (13) a process of reacting monohalogenobenzene with sulfur monochloride in the presence of zinc chloride to obtain dihalogenodiphenyl polysulfide, subsequently subjecting it to reduction reaction with hydrochloric acid-zinc (patent document 8), (14) a process of reacting 1,4-dihalogenobenzene with sodium hydrosulfide in 1-methyl-2-pyrrolidone (patent document 9), and so forth are known.
However, the processes of (11) to (14) cannot be satisfied as industrial manufacturing processes, because these processes have the following defects, (A) the yield is low, (B) isomers form, (C) high reaction temperature is required, (D) reagents that bear large environment loads such as chlorine or sulfide are used, and so forth.
Further, as a process for production of a benzothiophene derivative from a (phenylthio)acetic acid derivative or salts thereof, for example, the following processes are known, (15) a process of subjecting it to intramolecular ring closure reaction in the presence of Lewis acid, subsequently subjecting it to reduction reaction, subsequently subjecting it to dehydration reaction, and so forth (patent document 10).
However, in this process, the structure of produced compound is limited.
[Patent Document 1]
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